Oxyntomodulin: A cAMP-dependent stimulus of rat parietal cell function via the receptor for glucagon-like peptide-1 (7-36)NH2

We have previously shown that in highly enriched rat gastric parietal. cells the intestinal peptide hormones oxyntomodulin and glucagon-like peptide-2 (GLP-2) compete for receptor-binding with glucagon-like peptide-1 (GLP-1), a potent cAMP-dependent stimulus of H+ production in vitro. It is, however, unknown whether oxyntomodulin and GLP-2 elicit a biological. response by interacting with the GLP-1 receptor. Therefore, we used enriched rat parietal cells to investigate the effects of both hormones on the production of cAMP and H+ ([C-14]aminopyrine accumulation). Both parameters were stimulated by oxyntomodulin in a concentration-dependent manner. EC(50) values were 6.2 . 10(-8) and 2.5 . 10(-7) M oxyntomodulin for stimulation of H+ and cAMP production, respectively. The maximally effective concentrations for stimulation of [C-14]aminopyrine accumulation and cAMP production were 1 . 10(-6) and 1 . 10(-5) M oxyntomodulin, respectively. At these concentrations oxyntomodulin was nearly as effective as 10(-4) M histamine and equally effective as 10(-8) M GLP-1 (7-36)NH2. In the enriched parietal cell preparation there was no immunocytochemical evidence of contaminating D cells. Accordingly, the responses to oxyntomodulin and GLP-1 (7-36)NH2 were not augmented by incubating the cells in the presence of a polyclonal anti-somatostatin antibody. [C-14]Aminopyrine accumulation in response to oxyntomodulin was inhibited by the GLP-1 (7-36)NH2 receptor antagonist, exendin (9-39)NH2, but not by the H-2-receptor antagonist, ranitidine. Oxyntomodulin and carbachol acted additively to stimulate [C-14]aminopyrine accumulation. GLP-2 (10(-7) to 10(-5) M) was without effect on basal H+ and cAMP production; however, at 10(-5) M GLP-2 markedly inhibited oxyntomodulin-stimulated [C-14]aminopyrine accumulation. It is concluded that, by interacting with parietal cell receptors for GLP-1 (7-35)NH2, oxyntomodulin, but not GLP-2, directly stimulates H+ production by activating the adenylate cyclase.